Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplantation: An Interim Assessment.

Abstract

Purpose: The development of de novo donor specific antibody (DSA) following kidney transplantation is associated with worse long term graft survival. Although the mechanisms remain unclear it is believed that DSA binds to HLA expressed on graft endothelial cells (ECs) and activates complement, causing graft injury. There is no effective treatment for renal transplant recipients who have de novo DSA and worsening renal function. The current trial is designed to test if eculizumab, an antibody that blocks C5 cleavage, can ameliorate antibody-mediated injury by reducing EC injury. Methods: 10 kidney transplant recipients (4 control, 6 treatment), who had de novo DSA and had worsening renal function completed 6 months of either eculizumab therapy or observation, as a part of an ongoing clinical study. The primary endpoint is change in the trajectory of eGFR over the 6 months and secondary endpoints included pathologic changes, as well as, differential expression in endothelial cell-specific mRNAs (E-Selectin, vWf, END-1, CAV-1, CDH5 and PECAM-1) measured by qRT-PCR on kidney biopsy specimens. Results: Of the 4 control patients (3 C4d+ and 1 C4d-), 3 progressed to ESRD. Protocol biopsies showed fluctuating C4d staining and a progressive increase in IFTA grade. Of the 6 patients that received eculizumab (3 C4d+, 3 C4d-), all had stabilization of eGFR during 6 months of treatment. Five of these patients were also observed for 6 months following treatment, of which 4 patients had deteriorating renal function following cessation of eculizumab. There were no major complications associated with eculizumab therapy. Analysis of endothelial cell-specific mRNAs showed a 25 fold increase in E-Selectin expression in diseased kidneys compared to controls, however, eculizumab did not appear to affect expression of any of the endothelial cell-specific mRNA’s tested. Conclusion: Interim assessment of renal transplant patients with de novo DSA and worsening renal function show a stabilization in their renal function with eculizumab therapy. However, increased endothelial cell-specific mRNAs, possibly indicative of chronic antibody-mediated injury, may not be diminished by eculizumab therapy. DISCLOSURE:Kulkarni, S.: Grant/Research Support, Alexion Pharmaceuticals. Nancy, K.: Grant/Research Support, Alexion Pharmaceuticals. Formica, R.: Grant/Research Support, Alexion Pharmaceuticals. Moeckel, G.: Grant/Research Support, Alexion Pharmaceuticals. Pober, J.: Grant/Research Support, Alexion Pharmaceuticals.